Spatially Fractionated Radiation Therapy: Concepts, Delivery, Radiobiology, and Clinical Translation—A Critical Review

Spatially fractionated radiation therapy (SFRT) intentionally delivers highly non-uniform dose distributions to tumors, generating alternating high ("peaks") and low ("valleys") dose regions.Across multiple delivery modalities, including GRID therapy, Lattice therapy, minibeam radiation therapy (MBRT), and microbeam radiation therapy (MRT), SFRT aims to widen the therapeutic window by maintaining or enhancing tumor control while limiting normal-tissue toxicity.Over the past century, and especially in the two decades, an extensive body of clinical research (notably involving GRID and Lattice therapy) and preclinical studies (particularly with MBRT and MRT) has accumulated.These studies consistently demonstrate high rates of symptom relief in bulky or radioresistant tumors, promising local control when SFRT is combined with conventional radiotherapy, and remarkable normal-tissue tolerance at peak doses that would otherwise be prohibitive under uniform dose distributions.Mechanistically, SFRT appears to act through several complementary pathways: dose-volume effects that spare normal tissue within valleys; vascular responses that preferentially damage immature tumoral vessels while preserving normal microvasculature; immune activation and priming that support bystander and abscopal effects; and biochemical signaling mediated by reactive oxygen species gradients.From a physics perspective, SFRT requires dedicated dosimetry, consistent reporting of peak/valley metrics (including the peak-to-valley dose ratio), and careful management of small-field effects in MBRT and MRT.Current dose-prescription practices, often based on peak entrance or depth-of-maximum dose, lack strong biological justification.Converging evidence indicates valley dose and spatial parameters as key predictors of biological response.Future priorities include developing standardized planning and reporting frameworks.Other key goals involve establishing robust radiobiological models that integrate dose and immune effects, conducting prospective multicenter clinical trials, and advancing the practical translation of MBRT, MRT, and particle-based SFRT.This review synthesizes the historical development, delivery technologies, biological mechanisms, and clinical evidence of SFRT to outline a roadmap for its next phase of clinical translation.